Through a collaboration between the GRU Vascular Biology Center and the GRU Cancer Center, a novel therapeutic approach called ‘biased signaling’ has been brought from the cardiovascular field to that of ovarian cancer. The concept is based on the fact that G protein-coupled receptor (GPCR) signaling elicits multiple pathways with disparate effects. In particular, the endothelin type A receptor (ETAR) is a GPCR that is expressed in vascular smooth muscle cells and in cardiac tissues, as well as in tumors. In fact, ETARs are overexpressed in ovarian cancer, and this overexpression is associated with both late-stage cancer and the activation of metastatic genes. Accordingly, ETAR antagonists have been studied in clinical trials. However, these trials have been unsuccessful. GRU Vascular Biology Center and Cancer Center collaborators (Drs. Sangmi Kim, Guangyu Wu, Shuang Huang, and Nita Maihle) led by Dr. Il-man Kim hypothesized that the negative trial results stemmed from insufficient understanding of the pleiotropic signaling of GPCRs.
In a study published in Cellular Signalling, the collaborators demonstrated that activation of the ETAR in the HEY human metastatic ovarian cancer cell line generated both tumor suppressive and oncogenic effects: signaling through the Gαs subunit/cAMP/PKA pathway is tumor suppressive, while signaling through the Gαq subunit/PKC and the b-arrestin pathways is oncogenic. They also showed, for the first time, that ETAR/b-arrestin signaling activated two genes with metastatic/angiogenic functions (Calcrl and Icam2) – and that this activation is blocked by the Gαs subunit/cAMP/PKA pathway. Using Cancer Genome Atlas data, they show that Gαs overexpression corresponds with ovarian cancer patient survival. Overall, this research underscores the possibility of targeting ovarian cancer treatment through the biased activation of the ETAR- Gαs subunit/cAMP/PKA pathway.[Teoh JP, Park KM, Wang Y, Hu Q, Kim S, Wu G, Huang S, Maihle N, Kim IM. Endothelin-1/Endothelin A receptor-mediated biased signaling in human ovarian cancer. (2014) Cellular Signalling 26:2885-2895.]